The motivation and rationale for project 1 derives from the increasing recognition that ALS and related disorders represent syndromes with shared pathophysiological mechanisms, but a multitude of different (often genetic) causes. This realization is prompting an increasing interest in the ideas that one treatment may not be appropriate for all patients with each clinical syndrome, but rather that different therapeutic approaches might be needed depending on the underlying etiology of disease. It is against this background that defining the temporal course of disease and delineating the variability in rates of disease progression in genetically homogeneous patient populations has emerged as an essential stes in preparing for the future of clinical trials in ALS and related disorders. The principal goal of Project-1 of this RDCRC is to define the natural history (i.e. the temporal rate of disease progression) of disease in patients with ALS and related disorders who harbor different underlying genetic mutations; A secondary goal is to characterize the spatial and temporal patterns of disease progression within these individual disease categories, with a focus on ALS.